Cyclobenzaprine hydrochloride

Description

Cyclobenzaprine hydrochloride, USP is a tricyclic amine salt presented as a white to off-white, odourless, crystalline powder. Its molecular formula is C20H21N • HCl, and it has a molecular weight of 311.9. The compound has a melting point of 217°C and a pKa of 8.47 at 25°C. It is freely soluble in water, alcohol, and methanol; sparingly soluble in isopropanol; slightly soluble in chloroform and methylene chloride; and insoluble in n-hexane. Chemically, it is designated as 3-(5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Cyclobenzaprine hydrochloride tablets, USP are available in a strength of 10 mg for oral administration. Each 10 mg tablet contains cyclobenzaprine hydrochloride along with inactive ingredients including crospovidone, hypromellose, lactose anhydrous, macrogol, magnesium stearate, polysorbate 80, pregelatinized starch, silicified microcrystalline cellulose, and titanium dioxide. The tablets of 5 mg and 10 mg also contain D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Sunset Yellow FCF Aluminum Lake.

Uses and Indications

Cyclobenzaprine hydrochloride tablets, USP are indicated as an adjunct to rest and physical therapy for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. The therapeutic effect is characterized by the alleviation of muscle spasm and its associated signs and symptoms, including pain, tenderness, limitation of motion, and restrictions in activities of daily living.

This medication is intended for short-term use, specifically for periods not exceeding 2 to 3 weeks. There is insufficient evidence to support the effectiveness of cyclobenzaprine hydrochloride for prolonged use, as muscle spasms related to acute, painful musculoskeletal conditions are typically of short duration. Therefore, specific therapy for extended periods is seldom warranted.

Cyclobenzaprine hydrochloride tablets have not demonstrated efficacy in treating spasticity associated with cerebral or spinal cord diseases, nor are they indicated for use in children with cerebral palsy.

Dosage and Administration

The recommended dose of cyclobenzaprine hydrochloride tablets for most patients is 5 mg administered three times a day. Based on individual patient response, the dosage may be increased to 10 mg three times a day.

It is important to note that the use of cyclobenzaprine hydrochloride tablets for periods longer than 2 or 3 weeks is not recommended. For patients who are hepatically impaired or elderly, less frequent dosing should be considered to ensure safety and efficacy.

Contraindications

Use of this product is contraindicated in the following situations:

Patients with hypersensitivity to any component of the product should not use it due to the risk of severe allergic reactions.

Concomitant use with monoamine oxidase (MAO) inhibitors or within 14 days of their discontinuation is contraindicated, as this combination has been associated with hyperpyretic crisis, seizures, and fatalities in patients receiving cyclobenzaprine or similar tricyclic antidepressants.

The product is also contraindicated in individuals in the acute recovery phase of myocardial infarction, as well as those with arrhythmias, heart block or conduction disturbances, or congestive heart failure, due to potential cardiovascular complications.

Additionally, use is contraindicated in patients with hyperthyroidism, as it may exacerbate the condition.

Warnings and Precautions

The use of cyclobenzaprine hydrochloride is associated with significant warnings that healthcare professionals must consider to ensure patient safety.

Serotonin Syndrome Risk The concomitant use of cyclobenzaprine hydrochloride with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors, has been linked to the development of potentially life-threatening serotonin syndrome. The use of cyclobenzaprine hydrochloride in conjunction with MAO inhibitors is contraindicated.

Symptoms of serotonin syndrome may manifest as mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Should these symptoms occur, treatment with cyclobenzaprine hydrochloride and any concomitant serotonergic agents must be discontinued immediately, and supportive symptomatic treatment should be initiated.

If the clinical decision is made to continue treatment with cyclobenzaprine hydrochloride alongside other serotonergic drugs, careful observation is essential, particularly during the initiation of therapy or when increasing doses.

CNS Effects and Cardiac Risks Cyclobenzaprine is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. In short-term studies involving indications other than muscle spasm associated with acute musculoskeletal conditions, and typically at doses higher than those recommended for muscle spasm, serious central nervous system reactions similar to those observed with tricyclic antidepressants have been reported.

Tricyclic antidepressants are known to cause arrhythmias, sinus tachycardia, and prolongation of conduction time, which may lead to myocardial infarction and stroke. Therefore, caution is warranted when prescribing cyclobenzaprine, particularly in patients with a history of cardiovascular issues.

CNS Depressant Interactions Cyclobenzaprine may potentiate the effects of alcohol, barbiturates, and other central nervous system (CNS) depressants. Healthcare professionals should advise patients to avoid the use of these substances concurrently with cyclobenzaprine to mitigate the risk of enhanced CNS depression.

In summary, healthcare providers must remain vigilant regarding the potential for serotonin syndrome, CNS effects, and interactions with other medications when prescribing cyclobenzaprine hydrochloride.

Side Effects

Patients receiving treatment have reported a range of adverse reactions, categorized by frequency and seriousness.

Common adverse reactions, occurring in more than 3% of participants, include drowsiness (29% at 5 mg, 38% at 10 mg, compared to 10% in the placebo group), dry mouth (21% at 5 mg, 32% at 10 mg, 7% in the placebo group), fatigue (6% at both 5 mg and 10 mg, 3% in the placebo group), and headache (5% at both dosages, 8% in the placebo group).

Adverse reactions reported in 1% to 3% of patients encompass abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, decreased mental acuity, nervousness, upper respiratory infections, pharyngitis, fatigue/tiredness, asthenia, dyspepsia, unpleasant taste, blurred vision, and confusion.

Additional adverse reactions include serious events such as syncope and malaise, cardiovascular issues like tachycardia, arrhythmia, vasodilatation, palpitations, and hypotension. Digestive system reactions may involve vomiting, anorexia, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, and abnormal liver function, with rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity reactions can manifest as anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions include local weakness, while nervous system and psychiatric effects may involve seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Skin reactions may include sweating, and special senses may be affected by ageusia and tinnitus. Urogenital issues reported include urinary frequency and/or retention.

Certain adverse reactions have an unknown causal relationship, including chest pain and edema, hypertension, myocardial infarction, heart block, and stroke. Digestive issues such as paralytic ileus, tongue discoloration, stomatitis, and parotid swelling have also been noted. Endocrine reactions may involve inappropriate ADH syndrome, while hematologic and lymphatic concerns include purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions may present as fluctuations in blood sugar levels and weight changes. Musculoskeletal complaints can include myalgia, and nervous system and psychiatric effects may involve libido changes, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alterations in EEG patterns, and extrapyramidal symptoms. Respiratory issues such as dyspnea, skin reactions like photosensitization and alopecia, and urogenital concerns including impaired urination, urinary tract dilatation, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea have also been reported.

A significant warning includes the risk of serotonin syndrome, a potentially life-threatening condition that may occur when cyclobenzaprine hydrochloride is used in conjunction with other medications such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Symptoms may include mental status changes (e.g., confusion, agitation, hallucinations), autonomic instability (e.g., diaphoresis, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., tremor, ataxia, hyperreflexia, clonus, muscle rigidity), and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

In cases of overdose, common effects include drowsiness and tachycardia, while less frequent manifestations may involve tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Drug Interactions

Cyclobenzaprine is associated with significant drug interactions that warrant careful consideration.

Monoamine Oxidase Inhibitors (MAOIs) Cyclobenzaprine may lead to life-threatening interactions when administered concurrently with MAO inhibitors. It is essential to monitor patients closely for signs of serotonin syndrome, particularly when cyclobenzaprine is used alongside other serotonergic medications.

Central Nervous System (CNS) Depressants The concomitant use of cyclobenzaprine with alcohol, barbiturates, and other CNS depressants may enhance the sedative effects of these substances. Caution is advised, and dosage adjustments may be necessary to mitigate the risk of excessive sedation.

Tricyclic Antidepressants (TCAs) Tricyclic antidepressants may interfere with the antihypertensive effects of guanethidine and similar agents. Additionally, the use of TCAs in patients taking tramadol may increase the risk of seizures. Monitoring for these interactions is recommended to ensure patient safety and effective management of therapy.

Packaging & NDC

The table below lists all NDC Code configurations of Cyclobenzaprine Hydrochloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of cyclobenzaprine in pediatric patients below 15 years of age have not been established. Therefore, caution is advised when considering the use of this medication in this age group.

Geriatric Use

Elderly patients may experience increased plasma concentrations of cyclobenzaprine, necessitating careful consideration when prescribing this medication. A pharmacokinetic study indicated that mean steady-state AUC values for cyclobenzaprine in individuals aged 65 years and older were approximately 1.7-fold higher than those observed in younger adults. Notably, elderly male subjects exhibited the most significant increase, with levels approximately 2.4-fold higher, while elderly females showed a lesser increase of about 1.2-fold.

Given these pharmacokinetic differences, it is recommended that therapy with cyclobenzaprine in geriatric patients be initiated at a lower dose of 5 mg, with gradual titration to achieve the desired therapeutic effect.

Additionally, elderly patients may be at an elevated risk for central nervous system (CNS) adverse events, including hallucinations and confusion, as well as cardiac events that could lead to falls or other complications. There is also an increased potential for drug-drug and drug-disease interactions in this population.

Therefore, cyclobenzaprine should be prescribed to elderly patients only when clearly indicated, and close monitoring for adverse effects is advised throughout the course of treatment.

Pregnancy

Pregnancy Category B indicates that reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. However, there are no adequate and well-controlled studies in pregnant women.

Due to the limitations of animal reproduction studies in predicting human response, cyclobenzaprine should be used during pregnancy only if clearly needed. Healthcare professionals are advised to weigh the potential benefits against the risks when considering the use of this medication in pregnant patients.

Lactation

It is not known whether this drug is excreted in human milk. Due to the structural similarity of cyclobenzaprine to tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when administering cyclobenzaprine hydrochloride to lactating mothers. The potential effects on breastfed infants have not been established, and healthcare professionals should consider the risks and benefits of treatment in nursing women.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the insert text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to patients with reduced kidney function. Regular monitoring of renal function may be warranted in these patients, although specific guidelines are not outlined.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of cyclobenzaprine overdosage, although rare, fatalities may occur, particularly when multiple substances, including alcohol, are ingested deliberately. The onset of toxicity symptoms can be rapid, necessitating immediate hospital monitoring.

Symptoms of Overdosage

The most frequently observed effects of cyclobenzaprine overdose include drowsiness and tachycardia. Other less common symptoms may manifest, such as tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Critical manifestations, though rare, can include cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. Clinicians should be vigilant for changes in the electrocardiogram, particularly alterations in the QRS axis or width, as these are significant indicators of toxicity.

Management of Overdosage

All patients suspected of cyclobenzaprine overdose should undergo gastrointestinal decontamination. This includes performing a large volume gastric lavage followed by the administration of activated charcoal. If the patient's consciousness is impaired, securing the airway prior to lavage is essential, and emesis is contraindicated.

A maximal limb-lead QRS duration of ≥ 0.10 seconds may indicate the severity of the overdose. For patients exhibiting dysrhythmias or QRS widening, serum alkalinization to a pH of 7.45 to 7.55 is recommended. In cases of central nervous system (CNS) depression, early intubation is advised due to the risk of abrupt deterioration. Seizures should be managed with benzodiazepines or other anticonvulsants.

It is strongly recommended that healthcare professionals contact a poison control center for the most current information regarding treatment protocols for cyclobenzaprine overdose management.

Nonclinical Toxicology

Reproduction studies conducted in rats, mice, and rabbits at doses up to 20 times the human dose have shown no evidence of impaired fertility or teratogenic effects associated with cyclobenzaprine. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human responses, cyclobenzaprine should be used during pregnancy only if clearly needed.

At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Additionally, cyclobenzaprine did not exhibit mutagenic activity in male mice at dose levels of up to 20 times the human dose.

In long-term studies involving rats treated with cyclobenzaprine for up to 67 weeks at doses ranging from approximately 5 to 40 times the maximum recommended human dose, observations included pale and occasionally enlarged livers, along with dose-related hepatocyte vacuolation and lipidosis. These microscopic changes were noted in higher dose groups after 26 weeks and even earlier in rats that died prior to this time frame.

Cyclobenzaprine did not influence the onset, incidence, or distribution of neoplasia in an 81-week study in mice or in a 105-week study in rats.

Pharmacological studies in animals have demonstrated effects of cyclobenzaprine that are similar to those of structurally related tricyclic antidepressants. These effects include reserpine antagonism, norepinephrine potentiation, significant peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine was also associated with a slight to moderate increase in heart rate in animal studies.

Postmarketing Experience

The following adverse reactions have been reported in the postmarketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:

In the category of Body as a Whole, reactions such as syncope and malaise have been noted. Cardiovascular events include tachycardia, arrhythmia, vasodilatation, palpitation, and hypotension. Digestive system reactions consist of vomiting, anorexia, diarrhea, gastrointestinal pain, gastritis, thirst, flatulence, edema of the tongue, abnormal liver function, and rare reports of hepatitis, jaundice, and cholestasis.

Hypersensitivity reactions reported include anaphylaxis, angioedema, pruritus, facial edema, urticaria, and rash. Musculoskeletal reactions feature local weakness. The Nervous System and Psychiatric category includes seizures, ataxia, vertigo, dysarthria, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitement, paresthesia, diplopia, and serotonin syndrome. Skin reactions include sweating, while special senses reactions consist of ageusia and tinnitus. Urogenital reactions reported are urinary frequency and/or retention.

Additionally, other reactions have been reported rarely for cyclobenzaprine under circumstances where a causal relationship could not be established, or reported for other tricyclic drugs, and are included for alerting information to physicians. These include Body as a Whole reactions such as chest pain and edema; cardiovascular events like hypertension, myocardial infarction, heart block, and stroke; digestive issues including paralytic ileus, tongue discoloration, stomatitis, and parotid swelling. Endocrine reactions include inappropriate ADH syndrome.

Hematic and lymphatic reactions consist of purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia. Metabolic, nutritional, and immune reactions involve elevation and lowering of blood sugar levels, as well as weight gain or loss. Musculoskeletal reactions include myalgia. Nervous System and Psychiatric reactions feature decreased or increased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell's palsy, alteration in EEG patterns, and extrapyramidal symptoms. Respiratory reactions include dyspnea. Skin reactions also encompass photosensitization and alopecia. Urogenital reactions reported are impaired urination, dilatation of the urinary tract, impotence, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.

Patient Counseling

Healthcare providers should advise patients that cyclobenzaprine may impair mental and physical abilities necessary for performing hazardous tasks, including operating machinery or driving a motor vehicle, particularly when used in conjunction with alcohol or other central nervous system (CNS) depressants.

It is important to inform elderly patients that they may experience an increased frequency and severity of adverse events associated with cyclobenzaprine, whether or not they are taking other medications. For this population, healthcare providers should recommend initiating treatment with a 5 mg dose of cyclobenzaprine hydrochloride, with a gradual titration to higher doses as appropriate.

Patients should also be cautioned about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or monoamine oxidase (MAO) inhibitors.

Healthcare providers should ensure that patients are aware of the signs and symptoms of serotonin syndrome, and instruct them to seek immediate medical attention if they experience any of these symptoms.

Storage and Handling

The product is supplied in a tight, light-resistant container, compliant with USP standards, and features a child-resistant closure to ensure safety. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients using cyclobenzaprine should be aware that the medication may impair mental and physical abilities, particularly when combined with alcohol or other central nervous system (CNS) depressants, which can affect tasks such as operating machinery or driving. Clinicians should note that elderly patients are at an increased risk for adverse events, and it is recommended to initiate treatment with a 5 mg dose, titrating slowly as needed.

Additionally, patients must be informed about the potential risk of serotonin syndrome when cyclobenzaprine is used alongside other medications, including SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. They should be educated on the signs and symptoms of serotonin syndrome and advised to seek immediate medical attention if these occur.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Cyclobenzaprine Hydrochloride as submitted by Sportpharm LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)